Natural killer cells (NK) play an important role in immune defenses by their capacity to kill tumour cells or infected cells through natural cytotoxicity or to kill antibody coated target cells by a mechanism referred as the antibody dependent cellular cytotoxicity (ADCC) (reviewed in 1) (Renard). This mechanism appears to involve crosslinking of the NK FCxcex3RIIIa, rapid secretion of lytic factors (i.e., perforin/granzyme B) and expression of Fas-ligand which then triggers the apoptosis of targeted cells (2-9)(Vivier JI 91, Salcedo, Azzoni, Galandrini, Kanakaraj, Aramburu, Milella, Umera).
Although the mechanism of ADCC is well understood, little is known about the fate of the NK cells after the reaction and notably how the immune system regulates the activity of these cells functioning repeatedly after target cell lysis (10)(Ulberg). It was however recently demonstrated in vitro that some NK cells become inactivated and then died by apoptosis 24 to 48 hrs. after the ADCC reaction (11)(Jewett).
It has been demonstrated that Il-2 activated NK cells or LAK cells, but not naive NK cells undergo rapid apoptotic cell death after Fcxcex3RIIIa (12)(Orthaldo), CD94 (13)(Ida) or CD2 (14)(Ida) cross-linking with an antireceptor antibody, or after engagement in cytolytic functions (15)(Taga 1996). This activation induced cell death (AICD) of NK cells, that was suggested to contribute to the end of immune response, seemed to be dependent on the expression of Fas-ligand (16)(Eishen) or c-myc (17)(Azzoni).
In this application, it is described that apoptosis of freshly isolated NK cells occurs when the cells are treated in vitro with a mAb of which the Fc portion binds to their FcRxcex3IIIa and the antigen binding specificity to some CD2 or HLA class I membrane molecules. This apoptosis occurs rapidly, does not require RNA synthesis and is Fas/Fas-ligand independent.